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In supramolecular chemistry, host–guest chemistry describes complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds. Host–guest chemistry encompasses the idea of molecular recognition and interactions through noncovalent bonding. Noncovalent bonding is critical in maintaining the 3D structure of large molecules, such as proteins and is involved in many biological processes in which large molecules bind specifically but transiently to one another. There are four commonly mentioned types of non-covalent interactions: hydrogen bonds, ionic bonds, van der Waals forces, and hydrophobic interactions.
Contents
- Common host molecules
- Thermodynamic principles of hostguest interactions
- Association and dissociation constants
- Gibbs free energy dependency on K
- Experimental determination of HG using kinetics
- Nuclear magnetic resonance
- Raman spectroscopy
- Isothermal titration calorimetry
- UV vis spectroscopy
- Cooperativity
- Biological application
- Sensing
- Conformational switching
- Environmental applications
- References
Common host molecules
Common host molecules are cyclodextrins, calixarenes, pillararenes, cucurbiturils, porphyrins, metallacrowns, crown ethers, zeolites, cyclotriveratrylenes, cryptophanes, carcerands, and foldamers.
Host–guest chemistry is observed in inclusion compounds, Intercalation compounds, clathrates, and molecular tweezers.
Thermodynamic principles of host–guest interactions
There is an equilibrium between the unbound state, in which host and guest are separate from each other, and the bound state, in which there is a structurally defined host–guest complex:
The "host" component can be considered the larger molecule, and it encompasses the smaller, "guest", molecule. In biological systems, the analogous terms of host and guest are commonly referred to as enzyme and substrate respectively.
The thermodynamic benefits of host–guest chemistry are derived from the idea that there is a lower overall Gibbs free energy due to the interaction between host and guest molecules. Chemists are exhaustively trying to measure the energy and thermodynamic properties of these non-covalent interactions found throughout supramolecular chemistry; and by doing so hope to gain further insight into the combinatorial outcome of these many, small, non-covalent forces that are used to generate an overall effect on the supramolecular structure.
In order to rationally and confidently design synthetic systems that perform specific functions and tasks, it is very important to understand the thermodynamics of binding between host and guest. Chemists are focusing on the energy exchange of different binding interactions and trying to develop scientific experiments to quantify the fundamental origins of these non-covalent interactions by utilizing various techniques such as NMR spectroscopy, Raman spectroscopy, isothermal titration calorimetry, surface tension, and UV-Vis Spectroscopy. The experimental data are quantified and explained through analysis of binding constants Ka, Gibbs free energy ΔGo, Enthalpy ΔHo, and entropy ΔSo.
Association and dissociation constants
The association constant,
The equilibrium that has been established between the host–guest complex and free molecules can also be defined by a dissociation constant,
A Large
Gibbs free energy dependency on K
The Change in Gibbs free energy, ΔG, is a function of the equilibrium constant,
By knowing the association constant, the Gibbs free energy of the reaction can be solved.
One can also can see the dependency of Gibbs free energy on the macroscopic terms of enthalpy, ΔH and entropy, ΔS.
Experimental determination of [HG] using kinetics
In order to determine the concentration of the
Their occurs a problem because our association constant, which one wants to relate to the Gibbs free energy of the system, is a function of the concentration of host,
In order to overcome this obstacle, one can first make the alternative equilibrium approximation which states that the initial concentration of host molecules,
Solving for
This can be substituted into the original equilibrium equation
In solving for
Another assumption that is made in the determination of
With this final substitution, one can solve for the concentration of the host–guest complex
The final equation follows the form of the graph seen above. The plot above is called a binding isotherm which represents saturation kinetics and can be taken in two major parts.
At low concentrations of
At high concentrations of
The plot becomes independent of
This binding isotherm is one type of experimental data that can be analyzed and quantified by various spectroscopic imaging techniques; among others are Nuclear Magnetic Resonance (NMR), Raman Spectroscopy, and isothermal titration calorimetry. These spectroscopic methods can be help the scientist quantify the thermodynamic principles of host–guest chemistry.
Nuclear magnetic resonance
Nuclear magnetic resonance (NMR) is one of the most powerful spectroscopic techniques in analytical chemistry. It is an important tool for the studies of host–guest complexes, for elucidating the structures of the various complexes existing in the form of aggregates, ion pair or encapsulated systems. As the name suggests, NMR identifies the different nuclei in the molecules (most commonly, proton), by measuring their chemical shift. The binding activity of two molecules causes a considerable change in their electronic environments. This leads to a shift in the signals in the NMR spectrum, and this basic principle is made use of to study the phenomena of host–guest chemistry. The driving forces for host–guest binding are the various secondary interactions between molecules, such as hydrogen bonding and pi-pi interaction. Thus, NMR also serves as an important technique to establish the presence of these interactions in a host–guest complex.
Previous NMR studies have given useful information about the binding of different guest to hosts. Fox et al. calculated the hydrogen-bond interactions between pyridine molecules and poly(amido amine (PAMAM) dendrimer; on the basis of the chemical shift of the amine and the amide groups. In a similar study, Xu et al. titrated carboxylate based G4 PAMAM dendrimer (the host) with various amine based drugs (the guests) and monitored the chemical shifts of the dendrimer. In conjunction with the 2D-NOESY NMR techniques, they were able to precisely locate the position of the drugs on the dendrimers and the effect of functionality on the binding affinity of the drugs. They found conclusive evidence to show that the cationic drug molecules attach on the surface of anionic dendrimers by electrostatic interactions, whereas an anionic drug localizes both in the core and the surface of the dendrimers, and that the strength of these interactions are dependent on the pKa values of the molecules.
In a different study, Sun et al. studied the host–guest chemistry of ruthenium trisbipyridyl-viologen molecules with cucurbituril. Whilst monitoring the change in the chemical shifts of the pyridine protons on viologen, they found that the binding modes for the 1:1 complexes are completely different for different cucurbituril molecules. In cucurbit[7]uril, only four aromatic protons per single bipyridyl ligand take part in the binding process, whilst all the aromatic protons of the ligand form a part of the complex when cucurbit[8]uril is used.
However, an important factor that has to be kept in mind while analyzing binding between the host and the guest is the time taken for data acquisition compared to the time for the binding event. In a lot of cases, the binding events are much faster than the time-scale of data acquisition, in which case the output is an averaged signal for the individual molecules and the complex. The NMR timescale is of the order of milliseconds, which in certain cases when the binding reaction is fast, limits the accuracy of the technique.
Raman spectroscopy
Raman spectroscopy is a spectroscopic technique used in the study of molecules which exhibit a Raman scattering effect when monochromatic light is incident on it. The basic requirement to get a Raman signal is that the incident light brings about an electronic transition in the chemical species from its ground state to a virtual energy state, which will emit a photon on returning to the ground state. The difference in energy between the absorbed and the emitted photon is unique for each chemical species depending on its electronic environment. Hence, the technique serves as an important tool for study of various binding events, as binding between molecules almost always results in a change in their electronic environment. However, what makes Raman spectroscopy a unique technique is that only transitions which are accompanied by a change in the polarization of the molecule are Raman active. The structural information derived from Raman spectra gives very specific information about the electronic configuration of the complex as compared to the individual host and guest molecules.
Solution-phase Raman spectroscopy often results in a weak scattering cross-section. Therefore, recent advances have been made to enhance the Raman signals, such as surface enhanced Raman spectroscopy, and Resonance Raman spectroscopy. Such techniques serve an additional purpose of quantifying the analyte-receptor binding events, giving a more detailed picture of the host–guest complexation phenomena where they actually take place; in solutions. In a recent breakthrough, Flood et al. determined the binding strength of tetrathiafulvalene (TTF) and cyclobis(paraquat-p-phenylene) using Raman spectroscopy as well as SERS. Prior work in this field was aimed at providing information on the bonding and the structure of the resulting complex, rather than quantitative measurements of the association strengths. The researchers had to use Resonance Raman spectroscopy in order to be able to get detectable signals from solutions with concentrations as low as 1 mM. In particular they correlated the intensity of the Raman bands with the geometry of the complex in the photo-excited state. Similar to UV-vis spectroscopy based titration; they calculated the binding constant by “Raman titration” and fitted the binding curves to 1:1 models, giving a
Isothermal titration calorimetry
Spectroscopic techniques give information about the binding constant
provided that the experiment is carried out under isothermal conditions; hence the name isothermal calorimetry. The procedure is similar to a conventional titration procedure wherein the host is added sequentially to the guest and the heat absorbed or evolved is measured, compared to a blank solution. The total heat released, Q, corresponds to the association constant,
Which can be simplified as
Where
The above equation can be solved by non-linear regression analysis to obtain the value of
UV-vis spectroscopy
UV-vis spectroscopy is one of the oldest and quickest methods of studying the binding activity of various molecules. The absorption of UV-light takes place at a time-scale of picoseconds, hence the individual signals from the species can be observed. At the same time, the intensity of absorption directly correlates with the concentration of the species, which enables easy calculation of the association constant. Most commonly, either the host or the guest is transparent to UV-light, whilst the other molecule is UV-sensitive. The change in the concentration of the UV-sensitive molecules is thus monitored and fitted onto a straight line using the Benesi-Hildebrand method, from which the association constant can be directly calculated. Additional information about the stoichiometry of the complexes is also obtained, as the Benesi-Hilderbrand method assumes a 1:1 stoichiometry between the host and the guest. The data will yield a straight line only if the complex formation also follows a similar 1:1 stoichiometry. A recent example of a similar calculation was done by Sun et al., wherein they titrated ruthenium trisbipyridyl-viologen molecules with cucurbit[7]urils and plotted the relative absorbance of the cucurbit molecules as a function of its total concentration at a specific wavelength. The data nicely fitted a 1:1 binding model with a binding constant of
Cooperativity
Cooperativity is defined to be when a ligand binds to a receptor with more than one binding site, the ligand causes a decrease or increase in affinity for incoming ligands. If there is an increase in binding of the subsequent ligands, it is considered positive cooperativity. If a decrease of binding is observed, then it is negative cooperativity. Examples of positive and negative cooperativity are hemoglobin and aspartate receptor, respectively.
In recent years, the thermodynamic properties of cooperativity have been studied in order to define mathematical parameters that distinguish positive or negative cooperativity. The traditional Gibbs free energy equation states:
where:
It is considered that if
Biological application
Dendrimers in drug-delivery system is an example of various host–guest interactions. The interaction between host and guest, the dendrimer and the drug, respectively, can either be hydrophobic or covalent. Hydrophobic interaction between host and guest is considered “encapsulated,” while covalent interactions are considered to be conjugated. The use of dendrimers in medicine has shown to improve drug delivery by increasing the solubility and bioavailability of the drug. In conjunction, dendrimers can increase both cellular uptake and targeting ability, and decrease drug resistance.
The solubility of various NSAIDs increases when it is encapsulated in PAMAM dendrimers. This study shows the enhancement of NSAID solubility is due to the electrostatic interactions between the surface amine groups in PAMAM and the carboxyl groups found in NSAIDs. Contributing to the increase in solubility are the hydrophobic interactions between the aromatic groups in the drugs and the interior cavities of the dendrimer. When a drug is encapsulated within a dendrimer, its physical and physiological properties remains unaltered, including non-specificity and toxicity. However, when the dendrimer and the drug are covalently linked together, it can be used for specific tissue targeting and controlled release rates. Covalent conjugation of multiple drugs on dendrimer surfaces can pose a problem of insolubility.
This principle is also being studied for cancer treatment application. Several groups have encapsulated anti-cancer medications such as: Camptothecin, Methotrexate, and Doxorubicin. Results from these research has shown that dendrimers have increased aqueous solubility, slowed release rate, and possibly control cytotoxicity of the drugs. Cisplatin has been conjugated to PAMAM dendrimers that resulted in the same pharmacological results as listed above, but the conjugation also helped in accumulating cisplatin in solid tumors in intravenous administration.
Sensing
Traditionally, chemical sensing has been approached with a system that contains a covalently bound indicator to a receptor though a linker. Once the analyte binds, the indicator changes color or fluoresces. This technique is called the indicator-spacer-receptor approach (ISR). In contrast to ISR, Indicator-Displacement Assay (IDA) utilizes a non-covalent interaction between a receptor (the host), indicator, and an analyte (the guest). Similar to ISR, IDA also utilizes colorimetric (C-IDA) and fluorescence (F-IDA) indicators. In an IDA assay, a receptor is incubated with the indicator. When the analyte is added to the mixture, the indicator is released to the environment. Once the indicator is released it either changes color (C-IDA) or fluoresces (F-IDA).
IDA offers several advantages versus the traditional ISR chemical sensing approach. First, it does not require the indicator to be covalently bound to the receptor. Secondly, since there is no covalent bond, various indicators can be used with the same receptor. Lastly, the media in which the assay may be used is diverse.
Chemical sensing techniques such as C-IDA have biological implications. For example, protamine is a coagulant that is routinely administered after cardiopulmonary surgery that counter acts the anti-coagulant activity of herapin. In order to quantify the protamine in plasma samples, a colorimetric displacement assay is used. Azure A dye is blue when it is unbound, but when it is bound to herapin, it shows a purple color. The binding between Azure A and heparin is weak and reversible. This allows protamine to displace Azure A. Once the dye is liberated it displays a purple color. The degree to which the dye is displaced is proportional to the amount of protamine in the plasma.
F-IDA has been used by Kwalczykowski and co-workers to monitor the activities of helicase in E.coli. In this study they used thiazole orange as the indicator. The helicase unwinds the dsDNA to make ssDNA. The fluorescence intensity of thiazole orange has a greater affinity for dsDNA than ssDNA and its fluorescence intensity increases when it is bound to dsDNA than when it is unbound.
Conformational switching
A crystalline solid has been traditionally viewed as a static entity where the movements of its atomic components are limited to its vibrational equilibrium. As seen by the transformation of graphite to diamond, solid to solid transformation can occur under physical or chemical pressure. It has been recently proposed that the transformation from one crystal arrangement to another occurs in a cooperative manner. Most of these studies have been focused in studying an organic or metal-organic framework. In addition to studies of macromolecular crystalline transformation, there are also studies of single-crystal molecules that can change their conformation in the presence of organic solvents. An organometallic complex has been shown to morph into various orientations depending on whether it is exposed to solvent vapors or not.
Environmental applications
Host guest systems have been utilized to remove hazardous materials from the environment. They can be made in different sizes and different shapes to trap a variety of chemical guests. One application is the ability of p-tert-butycalix[4]arene to trap a cesium ion. Cesium-137 is radioactive and there is a need to remove it from nuclear waste in an efficient manner. Guest-host chemistry has also been used to remove carcinogenic aromatic amines, and their N-nitroso derivatives from water. These waste materials are used in many industrial processes and found in a variety of products such as: pesticides, drugs, and cosmetics.